Two proteins, human plasma BuChE, and a recombinant human BuChE are both in advanced development[unreadable] as potential prophylacitcs for proteting aginst chemical warfare agents. These proteins react rapidly and[unreadable] stoiciometrically to effectively scavenge the poisons in the blood stream but they require relatively large[unreadable] amounts of protein to provide protection. The challenge of identifying a protein based drug that would[unreadable] require less material while providing improved protection with the advantage of enhanced user acceptance[unreadable] cannot be ignored. Recent efforts in our laboratory have identified human paraoxonase (PON) as a protein[unreadable] that can catalyze the hydrolysis of all nerve agents and as a naturally occuring plasma enzyme should have[unreadable] an in vivo bioavailability of hours or days. As such it is an excellent candidate for phrophylactic administration[unreadable] to provide protection for first responders to a terorist attack or military forces in a civilian peacekeeping[unreadable] setting subject to an asymmetric threat. If it were administered intravenously it could also serve as a rapid-onset[unreadable] therapeutic antidote to a segment of the civilian popuation exposed to nerve agents. Preliminary[unreadable] studies have shown that these objectives are both feasible and obtainable. The cost/benefit ratio of such a[unreadable] drug is such that it is an excellent candidate for success and has the potential to be the first in a series of a[unreadable] novel class of drugs. We propose to use rational design to identify those amino acids critical for cataltyic[unreadable] activity and then, using site directe mutagenesis, enhance the native catalytic activity of human PON to[unreadable] create a viable candidate for transition to advancement to clinical trials within a five year period. This will[unreadable] address a critical gap in the national goal of protecting the civilian population against a terrorist-initiated[unreadable] chemical weapons attack.[unreadable] Current medical protection against chemical nerve agent exposure by terrorists is limited to post exposure[unreadable] treatment. We will identify and develop for clinical testing a human protein capable of providing rapid and[unreadable] long lasting prophylactic protection against exposure to chemical warfare nerve agents. Such a drug will[unreadable] address the critical national goal of providing improved protection to the general population against a[unreadable] terrorist-initiated chemical weapons attack.[unreadable]